US4318902A - Concentrated immunoglobulin solution suited for intravenous administration - Google Patents

Concentrated immunoglobulin solution suited for intravenous administration Download PDF

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US4318902A
US4318902A US06/110,038 US11003880A US4318902A US 4318902 A US4318902 A US 4318902A US 11003880 A US11003880 A US 11003880A US 4318902 A US4318902 A US 4318902A
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igm
solution
propiolactone
treatment
intravenous administration
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Wolfgang Stephan
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Biotest AG
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Biotest Serum Institut GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39591—Stabilisation, fragmentation
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S424/00—Drug, bio-affecting and body treating compositions
    • Y10S424/806—Drug, bio-affecting and body treating compositions involving IgM
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
    • Y10S530/827—Proteins from mammals or birds
    • Y10S530/829—Blood
    • Y10S530/83—Plasma; serum
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
    • Y10S530/827—Proteins from mammals or birds
    • Y10S530/829—Blood
    • Y10S530/83—Plasma; serum
    • Y10S530/831—Cohn fractions
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
    • Y10S530/827—Proteins from mammals or birds
    • Y10S530/832—Milk; colostrum
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
    • Y10S530/863—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof involving IgM

Definitions

  • the invention relates to a process for the preparation of an immunoglobulin solution suited for intravenous administration and containing IgM in somewhat concentrated form, wherein an IgM-containing protein fraction obtained by a conventional fractionating process from blood plasma or serum is treated with such amounts of ⁇ -propiolactone that the ratio of ⁇ -propiolactone to a 5% solution of the IgM-containing proteins is from about 0.05 to 0.15 ml per 100 ml, and is then worked up in known manner.
  • the IgM-containing immunoglobulin preparation prepared in accordance with the invention and suited for intravenous administration has a high antibody activity against gram-negative and gram-positive bacteria.
  • IgM antibody contains five Fc sites per molecule, in contrast to the IgG antibody which only contains one Fc site per molecule, it was to be expected that the anticomplementary activity of IgM-containing immunoglobulin preparations could be overcome only through a drastic increase in the concentration of the modifiers (enzymes and acylating agents), which, however, would result in a substantial loss of antibody activity, as has been shown by the example of chemical modification of IgG.
  • the intravenously compatible immunoglobulin solution containing IgM in concentrated form is free of anticomplementary activity and possesses high antibody activity against bacterial pathogens.
  • an IgM-containing protein fraction obtained by one of the conventional fractionating processes from blood plasma or serum is treated with such amounts of ⁇ -propiolactone that the ratio of ⁇ -propiolactone to a 5% solution of the IgM-containing proteins is from 0.05 to 0.15 ml per 100 ml.
  • IgM-containing fractions from Cohn's alcohol fractionation of human blood plasma, for example, or from the Rivanol (6,9-diamino-2-ethoxyacridine)/ammonium sulfate fractionation may be used as starting materials.
  • a particularly preferred starting material is Cohn Fraction III from human plasma.
  • Such an IgM-containing fraction is preferably first dissolved in a physiological (0.9%) sodium chloride solution to give an about 5% protein solution.
  • this protein solution Prior to the treatment with ⁇ -propiolactone, this protein solution should preferably be freed of lipids by a treatment with colloidal silica gel.
  • a treatment with crosslinked dextrans or cellulose having diethylaminoethyl groups, and preferably with the anion exchangers known as DEAE-Sephadex A-50 or DEAE cellulose, may also be carried out.
  • Precipitate III for example, from the Rivanol/ammonium sulfate fractionation is used as starting material, this precipitate may first be dissolved in water and dialyzed against a phosphate buffer solution of pH 6.2, and the euglobulin precipitate so obtained may then be dissolved in physiological saline solution.
  • the treatment with ⁇ -propiolactone is then carried out at temperatures ranging from about 20° to 37° C. and pH values between about 7 and 8.5, and preferably about 8, for about 2 to 10 hours, and preferably about 4 to 6 hours, until a constant pH value is obtained.
  • the solution obtained is worked up in known manner, for example, sterile filtered.
  • a treatment with activated carbon may first be carried out.
  • the anticomplementary activity corresponds to the values for commercial intravenously compatible preparations of the IgG type.
  • the antibody activity is largely preserved after the ⁇ -propiolactone treatment.
  • Cohn fraction III of human plasma was dissolved in 0.9% saline solution to give a 5% protein solution, freed of lipids with 3% Aerosil, and treated with 80 mg DEAE-Sephadex A-50 per gram of protein.
  • the solution which had a protein concentration of 5%, was then treated at pH 8.0 and 37° C. with 0.1 ml ⁇ -propiolactone per 100 ml of solution until a constant pH value was obtained.
  • the solution obtained was dialyzed in known manner against 0.9% saline solution and sterile filtered. It was then suited for intravenous administration.
  • Cohn fraction III of human plasma heated for 2 hours to 56° C. was dissolved in 0.9% saline solution to give a 5% protein solution, freed of lipids with 3% Aerosil, and treated with 80 mg DEAE-Sephadex A-50 per gram of protein.
  • the solution, whose protein concentration was 5%, was then treated at pH 8.0 and 37° C. with 0.05 ml ⁇ -propiolactone per 100 ml of solution until a constant pH value was obtained.
  • the solution obtained was worked up in known manner by means of dialysis and sterile filtration and was then suited for intravenous administration.
  • Cohn fraction III of human plasma was dissolved in 0.9% saline solution to give a 5% solution, freed of lipids with 3% Aerosil, and treated with 80 mg DEAE-Sephadex A-50 per gram of protein.
  • the solution was then diluted with 0.05 molar acetate buffer to 1.5% protein, adjusted to a pH of 4.8, and treated with 1.5 ml octanoic acid per 100 ml of solution and with 0.4 g Ca 3 (PO 4 ) 2 per 100 ml of solution.
  • Precipitate III from a Rivanol/ammonium sulfate fractionation was dissolved in water to give a solution having a protein concentration of 3%.
  • An euglobulin precipitation was then carried out by dialysis against 0.0005 molar phosphate buffer of pH 6.2. After the precipitate had been dissolved in 0.9% saline solution to give a 5% protein solution, the latter was treated with 0.15 ml ⁇ -propiolactone per 100 ml of solution at pH 8.0 and 37° C. until a constant pH value was obtained. Then it was sterile filtered.
  • the solution obtained was suitable for intravenous administration.

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Mycology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Immunology (AREA)
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Abstract

A process for the preparation of an immunoglobulin solution containing IgM in concentrated form and suited for intravenous administration, comprising treating an IgM-containing protein fraction obtained by conventional fractionation from blood plasma or serum with β-propiolactone in an amount such that the ratio of β-propiolactone to a 5% solution of the IgM-containing proteins is from about 0.05 to 0.15 ml per 100 ml. Advantageously, prior to the treatment with β-propiolactone the IgM-containing protein fraction is freed of lipids by treatment with colloidal silica gel and with crosslinked dextrans or diethylaminoethyl cellulose. The starting material used is a Cohn fraction III of human blood plasma which has been dissolved in physiological saline solution to a concentration of about 5% protein, the treatment with β-propiolactone is carried out at about 20° to 37° C. for about 4 to 6 hours until a substantially constant pH of about 8 is obtained, and the solution is thereafter sterile filtered.

Description

BACKGROUND OF THE INVENTION
The invention relates to a process for the preparation of an immunoglobulin solution suited for intravenous administration and containing IgM in somewhat concentrated form, wherein an IgM-containing protein fraction obtained by a conventional fractionating process from blood plasma or serum is treated with such amounts of β-propiolactone that the ratio of β-propiolactone to a 5% solution of the IgM-containing proteins is from about 0.05 to 0.15 ml per 100 ml, and is then worked up in known manner.
The IgM-containing immunoglobulin preparation prepared in accordance with the invention and suited for intravenous administration has a high antibody activity against gram-negative and gram-positive bacteria.
While a number of processes for the preparation of intravenously compatible immunoglobulin preparations of the IgG type and containing primarily antibodies against viruses has been developed, such as degradation by means of pepsin (Schultze, H. E., and G. Schwick, Dtsch. med. Wochenschrift 87, 1643 [1962]), degradation by means of plasmin (Barandun, S., et. al., Vox Sang. 28, 157 [1975]), degradation by means of hydrochloric acid (Barandun, S., et. al., Vox Sang. 7, 187 [1962]), or chemical modification by means of β-propiolactone (Stephan, W., Z. Klin. Chem. Klin. Biochem. 7, 282 [1969]), there is as yet no method that would permit the preparation of intravenously compatible, highly purified immunoglobulin preparations containing IgM in the concentrated form required for the control of bacterial infections, although IgM-containing fractions, such as Cohn Fraction III, have been available since the years 1940 to 1950 when alcohol-fractionation techniques were developed. The fact that nonetheless no intravenously compatible IgM concentrates have been made available up to now is probably attributable to the structural differences between the IgM and IgG molecules with respect to the interrelation between anticomplementary activity and intravenous incompatibility.
In the light of the present state of the art, a denaturation due to the fractionating process induces at the Fc site of the antibody molecule a so-called anticomplementary activity, which is responsible for the intravenous incompatibility of fractionated immunoglobulins that have been not been subjected to a special treatment. Since the IgM antibody contains five Fc sites per molecule, in contrast to the IgG antibody which only contains one Fc site per molecule, it was to be expected that the anticomplementary activity of IgM-containing immunoglobulin preparations could be overcome only through a drastic increase in the concentration of the modifiers (enzymes and acylating agents), which, however, would result in a substantial loss of antibody activity, as has been shown by the example of chemical modification of IgG.
SUMMARY OF THE INVENTION
Surprisingly, it has now been found that despite a buildup of the anticomplementarily active Fc sites of the IgM molecule its anticomplementary activity can be overcome with amounts of β-propiolactone as small as those used in the preparation of intravenously compatible immunoglobulin of the IgG type in accordance with German patent application DAS No. 17 92 555, namely, about 0.05 to 0.15 ml of β-propiolactone per 100 ml of a 5% immunoglobulin solution.
By the process of the invention, it thus becomes possible to render immunoglobulin solutions containing IgM in concentrated form intravenously compatible while largely preserving their antibody activities.
The intravenously compatible immunoglobulin solution containing IgM in concentrated form is free of anticomplementary activity and possesses high antibody activity against bacterial pathogens.
In the practice of the process in accordance with the invention, an IgM-containing protein fraction obtained by one of the conventional fractionating processes from blood plasma or serum is treated with such amounts of β-propiolactone that the ratio of β-propiolactone to a 5% solution of the IgM-containing proteins is from 0.05 to 0.15 ml per 100 ml. IgM-containing fractions from Cohn's alcohol fractionation of human blood plasma, for example, or from the Rivanol (6,9-diamino-2-ethoxyacridine)/ammonium sulfate fractionation may be used as starting materials. A particularly preferred starting material is Cohn Fraction III from human plasma. Such an IgM-containing fraction is preferably first dissolved in a physiological (0.9%) sodium chloride solution to give an about 5% protein solution. Prior to the treatment with β-propiolactone, this protein solution should preferably be freed of lipids by a treatment with colloidal silica gel. A treatment with crosslinked dextrans or cellulose having diethylaminoethyl groups, and preferably with the anion exchangers known as DEAE-Sephadex A-50 or DEAE cellulose, may also be carried out.
When Precipitate III, for example, from the Rivanol/ammonium sulfate fractionation is used as starting material, this precipitate may first be dissolved in water and dialyzed against a phosphate buffer solution of pH 6.2, and the euglobulin precipitate so obtained may then be dissolved in physiological saline solution. The treatment with β-propiolactone is then carried out at temperatures ranging from about 20° to 37° C. and pH values between about 7 and 8.5, and preferably about 8, for about 2 to 10 hours, and preferably about 4 to 6 hours, until a constant pH value is obtained.
After the treatment with β-propiolactone, the solution obtained is worked up in known manner, for example, sterile filtered. A treatment with activated carbon may first be carried out.
The favorable properties of the immunoglobulin solutions obtained by the process in accordance with the invention are demonstrated by the following tests.
(1) Anticomplementary activity
______________________________________                                    
                   Complement consumption                                 
                   (ml complement [1:30])                                 
Product            per 1 ml sample                                        
______________________________________                                    
IgM concentrate before treat-                                             
                   7                                                      
ment with β-propiolactone                                            
IgM concentrate after treat-                                              
ment with β-propiolactone                                            
(0.12 ml β-propiolactone per                                         
                   Max. 0.3                                               
100 ml)                                                                   
______________________________________
The anticomplementary activity corresponds to the values for commercial intravenously compatible preparations of the IgG type.
(2) Effect of β-propiolactone modification on bacterial antibody activities
______________________________________                                    
              Antibody activities                                         
                       After treatment                                    
                       with 0.12 ml                                       
                       β-propiolactone                               
              At       per 100 ml                                         
              start    5% solution                                        
Type            Score*     Score*                                         
of              (Strength of                                              
                           (Strength of                                   
bacteria        reaction)  reaction)  %                                   
______________________________________                                    
E. coli         36         38         105                                 
Klebsiella      37         26         70                                  
Pyocyaneus      38         37         97                                  
Streptococcus viridans                                                    
                46         34         74                                  
Streptococcus haemolyticus                                                
                40         30         75                                  
Enterococci     28         24         86                                  
Staphylococci   43         34         76                                  
______________________________________
The antibody activity is largely preserved after the β-propiolactone treatment.
(3) Comparison of the antibody activities of a commercial intravenously administered immunoglobulin preparation with those of the preparation in accordance with the invention
__________________________________________________________________________
         Antibody activities (score values) against                       
         E. Klebs-                                                        
                Pyo- Strept.                                              
                         Strept.                                          
                              Entero-                                     
                                   Staph'                                 
Preparation                                                               
         coli                                                             
            iella                                                         
                cyaneus                                                   
                     virid.                                               
                         haemol.                                          
                              cocci                                       
                                   cocci                                  
__________________________________________________________________________
Commercial                                                                
         14 9   11   1   0    0    3                                      
intravenous                                                               
immunoglobulin**                                                          
Intravenous                                                               
         38 26  37   34  30   24   34                                     
IgM concen-                                                               
trate in                                                                  
accordance                                                                
with invention                                                            
__________________________________________________________________________
 **Obtained by chemical modification with β-propiolactone.
(4) Comparison of the immunoglobulin composition of a commercial intravenously administered immunoglobulin preparation with that of an IgM concentrate in accordance with the invention
______________________________________                                    
                                      Anticomple-                         
                                      mentary                             
                                      activity                            
                                Total (ml                                 
                                protein                                   
                                      complement                          
                  IgA           content                                   
                                      [1:30]                              
Preparation                                                               
           IgG    (mg%)   IgM   (%)   per 1 ml)                           
______________________________________                                    
Commercial                                                                
intravenous                                                               
           4900   100     Traces                                          
                                5.0   0.3                                 
immunoglobulin*                                                           
Intravenous                                                               
IgM concentrate                                                           
           4000   500     500   5.0   0.3                                 
in accordance                                                             
with invention                                                            
______________________________________                                    
 *Obtained by chemical modification with β-propiolactone.
The examples which follow will serve to illustrate the invention.
EXAMPLE 1
Cohn fraction III of human plasma was dissolved in 0.9% saline solution to give a 5% protein solution, freed of lipids with 3% Aerosil, and treated with 80 mg DEAE-Sephadex A-50 per gram of protein. The solution, which had a protein concentration of 5%, was then treated at pH 8.0 and 37° C. with 0.1 ml β-propiolactone per 100 ml of solution until a constant pH value was obtained. The solution obtained was dialyzed in known manner against 0.9% saline solution and sterile filtered. It was then suited for intravenous administration.
EXAMPLE 2
Cohn fraction III of human plasma heated for 2 hours to 56° C. was dissolved in 0.9% saline solution to give a 5% protein solution, freed of lipids with 3% Aerosil, and treated with 80 mg DEAE-Sephadex A-50 per gram of protein. The solution, whose protein concentration was 5%, was then treated at pH 8.0 and 37° C. with 0.05 ml β-propiolactone per 100 ml of solution until a constant pH value was obtained. The solution obtained was worked up in known manner by means of dialysis and sterile filtration and was then suited for intravenous administration.
EXAMPLE 3
Cohn fraction III of human plasma was dissolved in 0.9% saline solution to give a 5% solution, freed of lipids with 3% Aerosil, and treated with 80 mg DEAE-Sephadex A-50 per gram of protein. The solution was then diluted with 0.05 molar acetate buffer to 1.5% protein, adjusted to a pH of 4.8, and treated with 1.5 ml octanoic acid per 100 ml of solution and with 0.4 g Ca3 (PO4)2 per 100 ml of solution. After centrifugation and dialysis against 0.9% saline solution, the supernatant was weakly concentrated and at a protein concentration of 5% treated at pH 8.0 and room temperature (20° to 25° C.) with 0.12 ml β-propiolactone per 100 ml of solution until a constant pH value was obtained. After treatment with charcoal, the solution was sterile filtered and was then suited for intravenous administration.
EXAMPLE 4
Precipitate III from a Rivanol/ammonium sulfate fractionation was dissolved in water to give a solution having a protein concentration of 3%. An euglobulin precipitation was then carried out by dialysis against 0.0005 molar phosphate buffer of pH 6.2. After the precipitate had been dissolved in 0.9% saline solution to give a 5% protein solution, the latter was treated with 0.15 ml β-propiolactone per 100 ml of solution at pH 8.0 and 37° C. until a constant pH value was obtained. Then it was sterile filtered. The solution obtained was suitable for intravenous administration.
It will be appreciated that the instant specification and examples are set forth by way of illustration and not limitation, and that various modifications and changes may be made without departing from the spirit and scope of the present invention.

Claims (10)

What is claimed is:
1. A process for the preparation of an immunoglobulin solution containing IgM in concentrated form and suited for intravenous administration, comprising treating an IgM-containing protein fraction obtained by conventional fractionation from blood plasma or serum with β-propiolactone in an amount such that the ratio of β-propiolactone to a 5% solution of the IgM-containing proteins is from about 0.05 to 0.15 ml per 100 ml.
2. A process according to claim 1, wherein the treatment with β-propiolactone is carried out for about 2 to 10 hours at a temperature ranging from about 20° to 37° C. and a pH between about 7 and 8.5.
3. A process according to claim 1, wherein the starting material used is a Cohn fraction III of human blood plasma which has been dissolved in physiological saline solution to a concentration of about 5% protein.
4. A process according to claim 1, wherein prior to the treatment with β-propiolactone the IgM-containing protein fraction is freed of lipids by treatment with colloidal silica gel and with crosslinked dextrans or diethylaminoethyl cellulose.
5. A process according to claim 1, wherein the treatment with β-propiolactone is carried out until a substantially constant pH value is obtained and the solution obtained is thereafter sterile filtered.
6. A process according to claim 4, wherein the starting material used is a Cohn fraction III of human blood plasma which has been dissolved in physiological saline solution to a concentration of about 5% protein, the treatment with β-propiolactone is carried out at about 20° to 37° C. for about 4 to 6 hours until a substantially constant pH of about 8 is obtained, and the solution is thereafter sterile filtered.
7. An intravenously injectable IgM-containing solution produced by the process of claim 1, having a maximum complement consumption per ml at a 30-fold dilution of 0.3, exhibiting at least about 70% of the antibody activity of the initial protein fraction against E. coli, Klebsiella, Pyocyaneus, Streptococcus viridans, Streptococcus haemolyticus, Enterococci and Staphylococci and having an IgM content of about 10% based on total globulins.
8. An intravenously injectable IgM-containing solution produced by the process of claim 6, having a maximum complement consumption per ml at a 30-fold dilution of 0.3, exhibiting at least about 70% of the antibody activity of the initial protein fraction against E. coli, Klebsiella, Pyocyaneus, Streptococcus viridans, Streptococcus haemolyticus, Enterococci and Staphylococci and having an IgM content of about 10% based on total globulins.
9. In the intravenous administration of IgM, the improvement which comprises employing an IgM-containing solution according to claim 7.
10. In the intravenous administration of IgM, the improvement which comprises employing an IgM-containing solution according to claim 8.
US06/110,038 1979-01-18 1980-01-07 Concentrated immunoglobulin solution suited for intravenous administration Expired - Lifetime US4318902A (en)

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DE2901882 1979-01-18
DE19792901822 DE2901822A1 (en) 1979-01-18 1979-01-18 METHOD FOR THE PRODUCTION OF AN IMMUNOGLOBULIN SOLUTION SUITABLE FOR THE INTRAVENOUS APPLICATION THAT IGM CONTAINS IN A CONCENTRATED FORM

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Cited By (24)

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US4370264A (en) * 1980-09-10 1983-01-25 Biotest-Serum-Institut Gmbh Method for the cold sterilization of preparations containing blood coagulation factor VIII
US4775638A (en) * 1985-05-08 1988-10-04 Centocor, Inc. Single vial technique for radiolabeling protein
US4841026A (en) * 1987-01-27 1989-06-20 Miles Laboratories, Inc. Virally inactivated, non-toxic, human transferrin preparation
US4877866A (en) * 1986-11-27 1989-10-31 Biotest Pharma Gmbh Method of producing a virus safe, storage-stable, and intravenously tolerable immunoglobulin-G preparation
US4880913A (en) * 1986-12-02 1989-11-14 Schwab & Co. Ges.M.B.H. Process for the preparation of an immunoglobulin which can be administered intravenously and is stable in liquid form
US5075425A (en) * 1989-08-17 1991-12-24 Biotest Pharma Gmbh Process for the preparation of a pharmaceutical which contains igg, iga and igm and can be administered intravenously
US5132406A (en) * 1986-05-19 1992-07-21 The Green Cross Corporation Method of producing immunoglobulin preparations for intravenous injection
US5157113A (en) * 1987-08-10 1992-10-20 Miles Inc. Removal of nucleic acids from monoclonal antibody preparations
US5190752A (en) * 1988-07-27 1993-03-02 Biotest Pharma Gmbh Intravenously administerable polyclonal immunoglobulin preparation containing igm and method of manufacture
US5219578A (en) * 1991-02-25 1993-06-15 Innovet, Inc. Composition and method for immunostimulation in mammals
US5510465A (en) * 1990-04-03 1996-04-23 Bayer Corporation Heat-treated IgM antibody preparations
EP0865793A1 (en) * 1997-03-19 1998-09-23 The Green Cross Corporation Immunoglobulin preparation and preparation process thereof
US6692739B1 (en) * 1998-08-31 2004-02-17 Inhibitex, Inc. Staphylococcal immunotherapeutics via donor selection and donor stimulation
US6939543B2 (en) * 1997-06-16 2005-09-06 Henry M. Jackson Foundation For The Advancement Of Military Medicine Opsonic and protective monoclonal and chimeric antibodies specific for lipoteichoic acid of gram positive bacteria
US20070049734A1 (en) * 2005-09-01 2007-03-01 Gene Zurlo Ultra-high yield intravenous immune globulin preparation
US20070049733A1 (en) * 2005-09-01 2007-03-01 Zurlo Eugene J Ultra-high yield intravenous immune globulin preparation
US20110152503A1 (en) * 2005-09-01 2011-06-23 Gene Zurlo Ultra-high Yield Of Alpha-1-Antitrypsin
US20110293638A1 (en) * 2010-05-26 2011-12-01 Baxter Healthcare S.A. Method to produce an immunoglobulin preparation with improved yield
WO2011131786A3 (en) * 2010-04-22 2011-12-22 Biotest Ag Process for preparing an immunoglobulin composition
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DE2901822A1 (en) 1980-07-31
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DE3061547D1 (en) 1983-02-17
EP0013901B1 (en) 1983-01-12

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